Submissions for variant NM_000249.4(MLH1):c.776T>C (p.Leu259Ser)

gnomAD frequency: 0.00002  dbSNP: rs56250509

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160527	SCV000211095	uncertain significance	not provided	2020-02-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: retains PMS2 binding ability (Wang 2012); Observed in an individual with a pediatric solid tumor in published literature (Chan 2018); This variant is associated with the following publications: (PMID: 30866919, 9057658, 24362816, 22252508, 30455982)
Counsyl	RCV000411294	SCV000488045	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2015-12-18	criteria provided, single submitter	clinical testing
Invitae	RCV000525411	SCV000625191	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 259 of the MLH1 protein (p.Leu259Ser). This variant is present in population databases (rs56250509, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182519). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 22252508). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000562377	SCV000669540	likely benign	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000562377	SCV000684863	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 259 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant protein retains the ability to bind PMS2 in a yeast two-hybrid assay (PMID: 22252508). This variant has been observed in at least two unrelated individuals with a likely pathogenic MLH1 covariant, however, the in cis or in trans phasing of the two variants is unknown (UMD record ID: 1120; Color internal data). This variant has been identified in 5/250852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000160527	SCV000805981	uncertain significance	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780420	SCV000917660	uncertain significance	not specified	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.776T>C (p.Leu259Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245718 control chromosomes (gnomAD), predominantly at a frequency of 0.00029 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.776T>C has been reported in the literature in a CML cell line (Hangaishi_1997). This report does not provide an unequivocal conclusion about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1989+1G>T (2X)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160527	SCV001134322	uncertain significance	not provided	2022-09-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00027 (5/18390 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, this variant has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MLH1)). Functional studies of this variant are inconclusive as it has been reported to have no effect on PMS2 binding in a yeast based assay (PMID: 22252508 (2012)), but has been reported to result in a significant change in MLH1 three dimensional protein confirmation via secondary structure analysis (PMID: 30866919 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000411294	SCV004018105	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000411294	SCV004190655	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998465	SCV004840904	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 259 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant protein retains the ability to bind PMS2 in a yeast two-hybrid assay (PMID: 22252508). This variant has been observed in at least two unrelated individuals with a likely pathogenic MLH1 covariant, however, the in cis or in trans phasing of the two variants is unknown (UMD record ID: 1120; Color internal data). This variant has been identified in 5/250852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.